tbuckley/cabot-search huggingface dataset:
RADT-03. A CASE OF PARTIAL HIPPOCAMPAL-AVOIDANCE WHOLE BRAIN RADIOTHERAPY IN A PATIENT WITH METASTATIC INFILTRATION OF THE LEFT HIPPOCAMPUS
Authors: Sandra Leskinen, Harshal Shah, Morana Vojnic, Beril Yaffe, Shonna Schneider, Randy D'Amico, A Gabriella Wernicke
Journal: Neuro-Oncology (2023)

Abstract In addition to surgical resection and systemic therapy, whole brain radiotherapy (WBRT) is a crucial modality in the treatment of cancers that have metastasized to the brain. It has been shown to improve intracranial disease control and overall survival. However, WBRT also increases the risk of radiation-associated damage to sensitive structures like the hippocampus, often resulting in neurocognitive dysfunction and decline. Hippocampal avoidance WBRT (HAWBRT) has been shown to reduce neurocognitive sequalae without worsening survival outcomes or increasing the risk of metastasis to the spared region compared to conventional WBRT. In cases where both hippocampi cannot be completely spared, the effectiveness of partial hippocampal avoidance on neurocognitive function and tumor control have been poorly described. We present the case of a patient diagnosed with triple negative invasive ductal carcinoma of the breast and disease metastatic to the brain, lung, bones, adrenal glands, and liver. Brain imaging revealed multiple brain metastases, two of which were noted near the left hippocampus. The patient underwent partial HAWBRT with complete avoidance of the right hippocampus and partial avoidance of the left. At 1-year follow-up, there was no evidence of metastasis in or near the partially spared left hippocampus. The patient’s neurocognitive functional status remained consistent with the findings of prospective randomized trials in which total bilateral hippocampal sparing was performed. To our knowledge, no such case has been presented in the literature. Further studies assessing the role of partial hippocampal avoidance in WBRT are needed.
PATH-29. CLINICAL OUTCOMES FOR YOUNG ADULTS WITH H3 G34-MUTANT GLIOMAS
Authors: Nikhil Mankuzhy, Luke Pike, Alexandra Miller, Brandon Imber
Journal: Neuro-Oncology (2023)

Abstract Diffuse hemispheric gliomas are rare brain tumors with mutations in H3F3A codon 34 which have recently been molecularly classified as their own entity. They are primarily diagnosed in adolescents and young adults and are generally associated with a poor prognosis. Given the limited published clinical data on young adults with H3 G34-mutant diffuse hemispheric glioma, we reviewed our institutional experience to evaluate clinical outcomes. We reviewed pathology reports and targeted sequencing results from patients at our institution for alterations in G34. All cases of patients 18 years or older were reviewed for baseline characteristics and clinical outcomes. Eleven patients were identified that followed at our institution since 2013. Median age at diagnosis was 24 (range 19-32) and nine were male. Three had multifocal intracranial disease at diagnosis, while 8 had localized disease. All but one underwent surgery, and all were treated with radiotherapy and temozolomide. Four received an additional investigative systemic agent for initial treatment. At time of review, 9 patients had recurred and median time to first recurrence was 6.4 months. Site of first failure was intracranial in all patients, of which three developed multifocal intracranial recurrence. Overall, 6 patients eventually developed multifocal intracranial disease and 1 patient developed leptomeningeal disease involving the spinal cord. Four patients received subsequent radiation to the brain and one received radiation to the spine. After progression, one patient received one subsequent line of systemic therapy, 7 patients received two lines, and one received three lines before they died of disease. Median overall survival from diagnosis was 20 months, and median survival from first failure was 11 months. For H3 G34-mutant glioma, survival is comparable to IDH WT Glioblastoma patients. These findings augment the existing literature on histone altered gliomas. Further investigation of patterns of failure is needed to guide optimal therapy.
BIOM-47. CLINICAL AND MOLECULAR FEATURES OF PATIENTS WITH LI-FRAUMENI SYNDROME AND GLIOMA: AN MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Keng Lam, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Li-Fraumeni Syndrome (LFS) predisposes patients for cancer, including gliomas, due to pathogenic TP53 germline variants. Little is known about their treatment course, molecular markers, and prognosis. METHODS This is a retrospective study of patients with diagnosis of LFS and glioma at MD Anderson Cancer Center from 2013 to 2023. Data collected includes next generation sequencing and treatment history. We analyzed descriptive statistics and Kaplan-Meier method to report their clinical characteristics and median progression-free survival (mPFS), defined as the time from initial diagnosis to first recurrence. RESULTS 14 patients with LFS had diagnosis of glioma, with half of them as the first manifestation of cancer. There were 8 IDH-mutant gliomas (all WHO grade 2 astrocytoma), 4 IDH-wildtype WHO grade 4 glioblastoma, and 2 gliomas with no molecular markers (WHO grade 3 astroblastoma and astrocytoma). Only IDH1 mutations were identified: R132H (n = 4), R132S (n = 2), and R132L (n = 2). ATRX status was tested in 12 gliomas, 8 with retained protein expression. ATRX co-mutation in IDH-mutant astrocytoma occurred in 38% of cases. TP53 status was tested in 12 gliomas, with 6 having positive expression on immunostaining. MGMT methylation status (n = 8) was detected in 2 IDH-mutant gliomas whereas all glioblastomas were unmethylated. For treatment, 7 patients with low-grade glioma opted for observation after initial diagnosis despite 5 being considered high-risk for recurrence (subtotal resection/ &amp;gt; 40 years of age). The mPFS for low-risk and high-risk low-grade astrocytoma on observation was 29.1 months and 28.5 months respectively. Based on IDH status, the mPFS for glioblastoma and IDH-mutant grade 2 astrocytoma was 6.4 months and 25.5 months respectively. CONCLUSIONS LFS patients may have glioma with higher incidence of non-canonical IDH1 mutations, lower likelihood of ATRX and IDH1 co-mutations, and less likely to be treated upfront after initial diagnosis despite having high risk profile for low grade glioma.
INNV-11. USE OF IVOSIDENIB IN THE TREATMENT OF LOW GRADE GLIOMAS
Authors: Anatevka Ribeiro, Douglas Ney
Journal: Neuro-Oncology (2023)

Abstract IDH 1 and IDH 2 are crucial metabolic enzymes which covert isocitrate to alpha-ketoglutarate. During this process, NADP is reduced to NADPH. Mutant IDH produces an oncometabolite, D-2 hydroxyglutarate (2-HG). Elevated 2-HG levels interfere with epigenetic regulation and cellular metabolism leading to oncogenesis and have been postulated to play a role in multiple malignancies. Mutations in IDH1 and IDH2 have been found in AML, cholangiocarcinoma, myeloproliferative, myelodysplastic syndromes, and low-grade gliomas. IDH inhibitors, although not FDA approved for treatment of glioma, have shown promise as a treatment for low-grade gliomas with IDH mutation in clinical trials. Ivosidenib is an orally available inhibitor of IDH1. We examined patients with oligodendroglioma treated off-label with ivosidenib. RANO criteria for low grade glioma was used to determine radiographic response following ivosidenib initiation. Patient ages 28 , 37 , and 37 females with oligodendroglioma, IDH1 mutated, 1p/19q co-deleted, WHO grade 2 were treated with ivosidenib. Treatment was initiated between August 2022 and March 2023. Two patients had two prior recurrences each while the third patient was treated in the neoadjuvant setting following subtotal resection. Two had stable disease as best response at follow-up of 7 and 17 months while the third is awaiting interval follow up. Duration of ivosidenib therapy was 9, 19, and 3 months respectively and is ongoing in all patients. Only grade 1 leukopenia was observed in one patient which resolved without intervention. No seizures since surgery were observed in two patients, while yearly focal seizures occurred in the third patient. Median progression free survival was not able to be determined, however preliminary data reveals stable disease as best response in all three patients without side effects or increased seizure frequency. IDH inhibitors continue to be an area of interest and ongoing research in the treatment of low-grade glioma.
IMMU-48. SOLUBLE CIRCULATING IMMUNE CHECKPOINT MOLECULES IN MALIGNANT BRAIN TUMORS
Authors: Alice Ryba, Cecile Maire, Richard Drexler, Katharina Kolbe, Sarina Heinemann, Klaus Pantel, Jens Gempt, Manfred Westphal, Franz L Ricklefs, Harriet Wikman-Kocher, Sabine Riethdorf, Katrin Lamszus, Malte Mohme
Journal: Neuro-Oncology (2023)

Abstract Immune checkpoint therapy has been shown to be effective in several types of cancer, and tumor-directed immune activation is also a promising strategy in glioblastoma (GBM) patients. Our goal was to discover alterations in the circulating immunome of GBM patients and other cerebral tumor entities to identify soluble immune biomarkers and novel therapeutic targets. We analyzed 30 markers in plasma of 208 patients and healthy donors, using bead-based multiplex assays and flow cytometry. In a smaller cohort we further applied a high-sensitivity discovery biomarker platform with 368 markers. We included patients with 1) primary GBM (n=68), 2) recurrent GBM (n=25), 3) cerebral metastases (NSCLC, n=61; breast cancer, n=19), 4) meningioma (n=15) as well as 5) healthy donors (HD, n=20). We detected a distinct immune signature in the peripheral blood of patients with GBM, which was defined by an increased prevalence of soluble immune checkpoint markers (sCD27, sPD-L2, sGal-9), whereas soluble chemokines (CX3CL, CXCL12) were underrepresented. This signature was similar in primary and recurrent GBM, but differed markedly from other cerebral tumor entities as well as from HD. Primary GBM, but not their recurrent counterparts, additionally exhibited increased levels of neurotrophic factors (BDNF, b-NGF) and signs of immune activation with significantly increased levels of IL-18. The biomarker discovery platform further identified 76 proteins that were specifically regulated in GBM compared to HD, offering the potential to serve as biomarkers for disease activity. GBM patients with higher levels of BDNF displayed a significantly shorter survival than patients with lower levels (9.33 vs. 21.90 months; p=0.0001). Likewise patients with high concentrations of VEGF survived significantly shorter than those with low concentrations (12.97 vs. 21.90 months, p=0,0166). Taken together, we were able to delineate a specific immune profile of soluble markers in GBM patients compared to other cerebral tumor entities and to healthy individuals.
NCOG-12. SURVIVAL OF THE ELDERLY: OUTCOMES OF VERY OLD GLIOBLASTOMA PATIENTS – RESULTS FROM AN AUSTRIAN MULTICENTER STUDY
Authors: Matthias Demetz, Constantin Hecker, Aleksandrs Krigers, Lukas Machegger, Johannes Kerschbaumer, Johannes Pöppe, Philipp Geiger, Antonio Spinello, Christoph J Griessenauer, Claudius Thomé, Christoph Schwartz, Christian Freyschlag
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma (GBM) outcomes in very old patients remain understudied. Limited data exist on outcomes and treatment options for this specific population, necessitating further research. Materials and METHODS We retrospectively analyzed all elderly GBM patients ( &amp;gt;65 years), who underwent treatment at two Austrian academic centers from 2007 to 2021. We conducted a comparative analysis between patients aged 65-79 years (old cohort) and a cohort of patients aged over 80 years (very old cohort). RESULTS 387 patients were included, 43 of them over 80 years of age at the time of surgery. Median preoperative Karnofsky Performance Score (KPS) amounted to 80, median preoperative tumor volume was 26.44cm3. Among elderly patients 283 (75%) underwent resection and 61 (25%) only biopsy. 66.5% of the elderly cohort underwent adjuvant treatment following the EORTC protocol. 88 patients (25.6%) experienced preoperative seizures. Among the very old cohort 29 patients (67%) underwent resection and 14 (33%) biopsy only. 42.5% received adjuvant treatment, 5 patients (11.6%) presented with preoperative epilepsy. Mean PFS was 8.9 months in old patients and 8.4 months in very old patients. Kaplan Meier Analysis revealed a mean OS of 12.8 vs 10.7 months respectively. Elderly patients showed significantly better preoperative KPS (p=0.033) as well as higher preoperative tumor volumes (p=0.039). Old patients showed significantly higher incidences of both preoperative (p=0.043) and postoperative (p=0.032) epilepsy. Furthermore, old patients underwent significantly more often resection (p=0.020) and adjuvant therapy (p=0.009) compared to very old patients. However, survival analysis showed no statistic differences regarding PFS and OS between the two groups (p &amp;gt;0.05). CONCLUSION Despite preexisting unfavorable prognostic features, we could not find any significant differences between old and very old GBM patients. Hence, the treatment of glioblastoma in very old patients should adopt a more inclusive approach considering the patient's overall health status and comorbidities.
BIOM-35. IDENTIFICATION AND VALIDATION OF POTENTIAL BIOMARKERS FOR DECITABINE-MEDIATED SENSITIZATION TO TEMOZOLOMIDE IN GLIOBLASTOMA
Authors: Thenzing Silva Hurtado, Julio Inocencio, Andy Mead, Gang Fang, Balagopal Pai, Nadejda Tsankova, Raymund Yong
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is an aggressive form of brain cancer with limited treatment options and a poor prognosis. Our previous research demonstrated that the DNA hypomethylating agent decitabine (DAC) enhances the sensitivity to temozolomide (TMZ) of a subset of primary GBM cell lines derived from fresh surgical tissue specimens, and that this effect may be mediated by upregulation of DNA mismatch repair genes including MLH1. In this context, we aim to identify additional biomarkers for DAC-mediated sensitization to TMZ with potential clinical utility through in vitro and in vivo experiments. We performed single cell RNA sequencing on three DAC-sensitized and three DAC-desensitized cell lines and found 4 genes that exhibited significant differential expression: DCN, LUM, CRABP2 and NUPR1. We validated these findings using quantitative immunoblots, RT-qPCR and immunohistochemistry, finding that NUPR1 protein expression levels varied most significantly between DAC-sensitized and desensitized GBM tissues. Long-range direct methylation sequencing of non-amplified genomic DNA enriched using CRISPR/Cas9 demonstrated several CpG sites within the 4 genes that may be predictive of TMZ sensitization response after treatment with DAC. Finally, we performed mouse survival experiments using orthotopic patient-derived xenografts (PDXs) of the six GBM cell lines, with preliminary results showing that in selected PDX survival was significantly increased with combined DAC-TMZ versus TMZ monotherapy as predicted by in vitro assays. In conclusion, our study demonstrates that combining DAC with TMZ may be a potential treatment strategy for GBM in a subset of patients. There likely exist several biomarkers that can be used at the time of diagnosis, alone or in combination, to predict the response to epigenetic preconditioning using DAC for TMZ sensitization, which will be necessary for optimal patient selection in an early phase clinical trial. Further data and validation studies are necessary to strengthen these findings and to confirm their clinical relevance.
BIOM-24. PREDICTION OF DISTANT RECURRENCE IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD THERAPY
Authors: Shivani Chiranth, Anouk Trip, Ib Christensen, Kirsten Grunnet, Søren Møller, Benedikte Hasselbalch, Aida Muhic, Ulrik Lassen, Hans Poulsen, Thomas Urup
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Infiltrative growth is a hallmark of glioblastoma (GBM) and is a major factor in therapeutic failure. We aimed to identify clinical and molecular factors associated with distance recurrence in glioblastoma patients treated with standard therapy (radiotherapy with concomitant and adjuvant temozolomide). METHODS Two prospective cohorts of consecutive, non-selected GBM patients administered standard therapy as primary treatment between year 2005-2016 (Cohort 1) and 2016-2021 (Cohort 2) at Rigshospitalet, Copenhagen were included. Distant recurrence was defined as a new contrast-enhancing tumor &amp;gt; 2 cm from the gross tumor volume. Clinical and molecular factors were screened for association with time to distant recurrence using univariate Cox regression analysis. The final model was generated employing multivariate analysis. RESULTS Cohort 1 and 2 included 628 and 395 patients, respectively. Out of the recurrence pattern evaluable patients, distant recurrence was observed in 117 patients (23%) in Cohort 1 and 73 patients (22%) in Cohort 2. PRELIMINARY RESULTS In Cohort 1, multivariate analysis showed that corticosteroid use, age, multifocal disease, ECOG performance status, and degree of tumor resection were not associated (p &amp;gt; 0.10) with distant recurrence. Two factors were independently associated with a higher likelihood of distant recurrence, namely non-methylated promoter of the MGMT gene (HR = 1.93; 95% CI:1.27-2.95; p = 0.002) and positive expression of Epidermal Growth Factor Receptor (EGFR) (HR = 3.70; 95% CI: 1.61-8.33; p = 0.002). In Cohort 2, the EGFR status was not available but the association of non-methylated MGMT with distant recurrence was validated (HR = 2.67; 95% CI: 1.62-4.42; p = 0.0001). CONCLUSION Non-methylated MGMT and positive EGFR expression were independent predictors of distant recurrence. Non-methylated MGMT was validated in Cohort 2 and can be used for risk stratification and to enrich clinical trials aiming at improved local or distant tumor control.
BIOM-41. CITRULLINATED HISTONE H3 ELISA REVEALS NETOSIS AS A SOURCE OF PROGNOSTIC CIRCULATING CELL-FREE DNA IN GLIOBLASTOMA
Authors: Jacob Till, Dominique Ballinger, Zhuoyang Wang, Zachariya Yazdani, Camilla Macia, Melinda Yin, Aseel Abdalla, Ali Nabavizadeh, Arati Desai, Zev Binder, Kandace Gollomp, Wanding Zhou, Erica Carpenter, Stephen J Bagley
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We have previously shown that higher concentrations of plasma cell free DNA (cfDNA), both at baseline and following chemoradiotherapy, are associated with worse survival in GBM. Because only scant amounts of GBM-derived cfDNA shed into the peripheral circulation, we sought to determine the predominant source of prognostic plasma cfDNA in these patients and hypothesized that this may help unravel the mechanism underlying the association of high cfDNA and survival. METHODS Plasma was obtained for 126 patients prior to resection of newly diagnosed GBM. A subset of 46 plasma samples had ccfDNA extracted, enzymatically converted, whole genome amplified, and analyzed on the Illumina Epic array for deconvolution of cfDNA methylation patterns. Based on these results demonstrating neutrophils as the predominant cfDNA source, we performed ELISA for citrullinated-histone 3 (citH3) in plasma from 113 of the patients as a specific marker of NETosis, a pro-tumor process of programmed neutrophil cell death during which DNA is released in web-like structures called neutrophil extracellular traps (NETs). RESULTS Deconvolution of cfDNA methylation patterns revealed that neutrophils were the dominant source of cfDNA (median percentage of cfDNA derived from neutrophils = 46% , range 17-67%) and correlated with baseline plasma cfDNA concentration (n = 46, r = 0.35, p = 0.017). Additionally, cfDNA concentration was significantly correlated with the concentration of citH3 (n = 113, r = 0.60, p &amp;lt; 0.0001), which was higher in GBM patients compared to 26 healthy controls (p &amp;lt; 0.0001). CONCLUSION Our findings suggest that NETosis may be the dominant source of plasma cfDNA, which we have previously shown to be highly prognostic in patients with GBM. Additional studies interrogating the tumor microenvironment for NETosis in GBM tumors are ongoing. These results lay the foundation for further exploration of NETosis as a therapeutic target and underscore the emerging importance of neutrophil biology in GBM.
EPID-11. THE IMPACT OF THE COVID-19 PANDEMIC ON TREATMENT PATTERNS IN GLIOBLASTOMA
Authors: Corey Neff, Mackenzie Price, Gino Cioffi, Kristin Waite, Carol Kruchko, J Bryan Iorgulescu, Jill Barnholtz-Sloan, Quinn Ostrom
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The COVID-19 pandemic and subsequent shutdowns led to significant disruptions in medical care and access to treatment for all medical conditions in the US in 2020. Institutional cohorts and survey-based studies have shown that there was significant care disruption for individuals diagnosed with primary brain tumors. In this analysis, we utilized a database containing ~80% of brain tumor diagnoses to assess the national impact of the pandemic on treatment patterns for glioblastoma. METHODS Data on newly diagnosed glioblastoma were obtained from the National Cancer Database, which includes hospital registry data from Commission on Cancer accredited facilities, for diagnosis years 2018-2020. Logistic regression was used to generate odds ratios (OR) of receiving resection, chemotherapy, or radiation after diagnosis in 2020 as compared to 2018-2019, after adjustment for potential confounders, including age at diagnosis, sex, race and ethnicity, insurance status, income, patient distance from diagnosing facility, Charlson comorbidity score, facility type and location, and MGMT methylation. RESULTS There were 7,184 glioblastoma, of which 5,873 were IDH-wt, diagnosed in 2020, a 3% decrease from the 2018-2019 average. For individuals with any newly diagnosed glioblastoma, there was a decrease in odds of resection (OR=0.91, p=0.047). Among those with any glioblastoma and a subset with IDH-wt glioblastoma there was a reduction in odds of radiation (OR=0.87, p=0.004 and 0.85, p&amp;lt; 0.001, respectively) and chemotherapy (OR=0.87, p=0.002 and 0.89, p=0.026, respectively). No decrease in odds of treatment was associated with a prior positive SARS-CoV-2 PCR test. CONCLUSIONS The COVID-19 pandemic caused significant disruption to health care for cancer patients in the US in 2020. For individuals with glioblastoma, in-person treatments decreased in frequency for individuals diagnosed in 2020 as compared to prior years. Further research is required to determine the impact this treatment disruption had on outcomes.